The broad goal of Project 1 of the Brigham/Harvard SCORE Center for Stress and Neural Regulation of Reproductive Aging Health Outcomes is to advance the health of postmenopausal women by determining stress responsivity in vasomotor symptoms (VMS) occurrence and persistence and to characterize neural processes and neurobiological mechanisms linking VMS with stress responsivity. VMS are the most common symptoms during and after menopause, occurring in up to 85% of women, lasting 7.4?9.0 years on average, and persisting for 10+ years in 33?40% of postmenopausal women. Investigations of stress mechanisms underlying VMS have important public health significance due to their high prevalence, impact on quality of life, and adverse health correlates. VMS disrupt sleep and are associated with cardiometabolic disease, which, together with risks of hormone therapy used to treat VMS, increase susceptibility to dementia in aging women. We propose a novel conceptualization of VMS as a chronic stress condition based on our preliminary data and that of others indicating associations of stress responsivity with VMS. Differences in responsivity to evoked stress tasks in women with VMS suggest underlying disruptions in stress-related neural networks (e.g., anterior cingulate cortex, hippocampus, orbitofrontal cortex, insula) and in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which regulates stress networks, as is seen in chronic stress conditions (e.g., anxiety, pain). Dysregulated stress responses may reflect neural processes through which stress mediates VMS. Project 1 will innovatively combine the robust methodology of an evoked stress paradigm with state-of-the-art functional magnetic resonance imaging and magnetic resonance spectroscopy to cross-sectionally investigate acute stress responsivity, neural network function, and GABA concentrations in women with and without VMS referred by Project 2 (Project Viva cohort). We will determine longitudinally whether dysregulation of neural stress networks and GABA predict persistence of VMS over a 2-year follow-up period. In conjunction with the Sleep Resource Core (SRC), we will examine whether sleep disruption comorbid with VMS further blunts acute stress responsivity. Similarly, we will test whether perceived stress contributes differentially to stress response dysregulation in those with VMS. Project 1 is integrated within the Brigham/Harvard SCORE, through enrolling participants and obtaining relevant longitudinal data from the Project 2 cohort, examining mechanistic neural stress processes underlying VMS in parallel with Project 3, utilizing sleep metrics obtained by the SRC, and teaching and mentoring junior faculty and trainees through the Career Enhancement Core. Leveraging these synergistic SCORE and extensive Brigham/Harvard institutional resources, our study will make major contributions to the health of aging women by identifying neural stress mechanisms linked to VMS?potentially pointing to novel treatments for VMS that may also improve sleep and cardiometabolic health, with downstream implications for dementia susceptibility in aging women.